The behavioral pharmacological profile of a drug in a pertinent species is necessary to evaluate quantitatively how the drug functions as a reinforcer or a punisher as well as to establish its stimulus effects. Schedules of food presentation with both fixed-interval and fixed-ratio components have been used most frequently in this type of study since they generate a wide range of rates and patterns of responding within a session and provide stable long-term baselines for chronic studies in individual animals. The present project involves the assessment of both the acute and chronic effects of a variety of drugs on schedule-controlled behavior. We have recently shown that the enhanced sensitivity which occurs to opioid antagonists on schedule-controlled behavior is pharmacologically specific, with cross-sensitivity occurring only to pure opioid antagonists. Further, we have demonstrated that this enhanced sensitivity is associated with an up-regulation of GABA receptor function in the cerebellum and of delta receptors in the hindbrain. Genetic factors are known to influence the behavioral effects of a number of different drugs, and studies of the interactions between environmental and genetic components that potentially affect the development of behavioral tolerance and sensitivity are being initiated. Behaviorally active drugs can also serve as discriminative stimuli to guide behavioral choice. Ongoing two- and three-lever drug discrimination projects in the laboratory have helped to define and characterize the spectrum of behavioral effects produced by a drug, to characterize the relative potency and efficacy to produce drug-like effects, and to evaluate a drug's mechanisms of action at the receptor level. Since most human drug-taking behavior involves chronic long-term use of an illicit drug or non-medical abuse of a prescribed medication, the consequences of chronic administration of drugs on schedule-controlled behavior and the discriminative functions of drugs are also being evaluated. Although the development of tolerance and dependence are related to pharmacological factors, tolerance can also be modified by environmental factors. For example, the interaction between drug administration and the ability to perform the task can result in differential tolerance that is a function of chronic daily dose and duration of treatment.